The classical approach to treat obesity, fatty liver and metabolic syndrome involves dietary calorie restriction, exercise, and, if necessary, bariatric surgery. Most diets focus on reducing energy intake, usually by restricting carbohydrates, proteins, and/or fat. Nutritional guidelines, such as the USDA MyPlate (food pyramid), focus on the caloric content of foods, such as proteins, grains, fruits, vegetables and dairy products. While most diets teach us how to count the calories we eat, rarely is weight loss sustained. It appears like something may be missing. In this proposal, we hypothesize that the non-caloric component of foods has an important, yet unrecognized, role in increasing the risk for obesity, fatty liver and insulin resistance. Based on our preliminary data, we propose that dietary salt, a noncaloric micronutrient present in many foods, has a role in influencing whether carbohydrates will act as simple caloric source or will initiate a metabolic system leading to fatty liver, insuln resistance, decreased leptin sensitivity, and weight gain. We hypothesize that the mechanism whereby dietary salt controls carbohydrate metabolic effects is mediated by its ability to hypertonically up-regulate and activate the aldose reductase-fructokinase system in liver, adipose tissue and brain. Aldose reductase up-regulation is mediated by the activation of the transcription factor associated to hypertonicity TonEBP/NFAT5 that stimulates the transcription of aldose reductase among other osmo-regulated genes. Activation of aldose reductase in these organs results in the generation of endogenous sorbitol and fructose from glucose. Metabolism of this endogenous fructose through fructokinase drives fat production and insulin resistance in the liver while inducing leptin release in adipose tissue and central decreased leptin sensitivity n the hypothalamus. Aim 1 will test the hypothesis that salty foods raise hepatic and blood tonicity, thereby activating TonEBP, aldose reductase and the fructokinase pathway. This activation leads to endogenous fructose production, fat accumulation and insulin resistance. Also, we will study if this process occurs in animals when salt intake is provided under isoosmolar conditions. Aim 2 will test the hypothesis that salt-induced metabolic syndrome (especially insulin resistance and fatty liver) can occur in isocaloric conditions. Also, we will tst if reduced central leptin sensitivity is an important step in the pathogenesis of salt-induced metabolic syndrome These studies may modify current views on the role of nutrition in obesity and metabolic syndrome, by revealing the importance of the non-caloric component of foods. While simple in concept, our studies could modify current scientific paradigms for nutrition and diet that could lead to changes in food labeling, nutrition and the dietary management of individuals who are overweight or obese.